In spite of the advances in health care and particularly perinatology, the preterm delivery of babies continues to be a major public health problem because of its association with infant morbidity and mortality. For example, the results of a multicenter trial spanning several years of experience showed that infants born prematurely, i.e., between 20 and 36 weeks gestation, accounted for 9.6% of births (Copper et al. Amer. J. Obstet. Gynecol. 168: 78, 1993). In that study, 83% of infant deaths occurred in gestations delivering prior to 37 weeks, and 66% involved gestations of less than 29 weeks.
Serious neonatal complications also decrease as the period of gestation increases. The incidence of neonatal respiratory distress syndrome decreases markedly after 36 weeks of gestation. Likewise, the incidence of neonatal patent ductus arteriosus and necrotizing enterocolitis decreases markedly after 32 weeks of gestation. According to Creasy, "high grade intraventricular hemorrhage diminishes rapidly after 27 weeks and is virtually absent after 32 weeks" (Creasy, Amer. J. Obstet. Gynecol. 168: 1223, 1993). Thus, extending the length of pregnancy beyond 32 weeks and preferable beyond 36 weeks could reduce the incidence of neonatal morbidity and virtually eliminate major causes of neonatal mortality.
According to Creasy, the incidence of preterm delivery in the United States is rising. When preterm delivery is defined as births occurring before 37 weeks of gestation, the incidence has risen from 9.4% in 1981 to 10.7% in 1989, accounting for approximately 425,000 of the 4,000,000 annual births in the United States of America.
There are several problems related to the rising incidence of preterm delivery in the United States. One problem is that physicians are unable to accurately predict which pregnancies are at risk. Factors known to be associated with elevated chronic risk of preterm delivery in otherwise asymptomatic women are low maternal socioeconomic status, lack of prenatal care, illicit drug use during pregnancy, previous preterm delivery, assisted reproductive techniques used in the current pregnancy (such as in vitro fertilization or gamete intra-fallopian transfer), smoking, uterine anomalies, and stress. (Morrison, Amer. J. Obstet. Gynecol. 168:538, 1993; Creasy, Amer. J. Obstet. Gynecol. 168:1223, 1993). Unfortunately, the majority of preterm births cannot be related to obvious causes, and even known causes may not necessarily be detectable or correctable. In fact, approximately one half of all preterm births occur in women who are pregnant for the first time and have no known risk factors for preterm delivery.
Even when women complain of symptoms frequently associated with acute risk of preterm delivery, it is often difficult to distinguish harmless symptoms from those associated with imminent prematurity. Many symptoms such as uterine contractions, change in vaginal discharge, abdominal discomfort, pelvic heaviness or change in cervical dimensions (effacement and dilatation) may harmlessly occur as normal variants in some pregnancies, while similar symptoms in other pregnancies can be associated with impending preterm delivery.
The majority of pregnant women who seek unscheduled emergency obstetrical care have complaints of excessive or painful uterine contractions of the uterus. Another frequent complaint is a tightening or pressure sensation which can indicate Braxton Hicks contractions of the uterus. Thus, physicians are often faced with the diagnostic dilemma of differentiating "true" from "false" labor with clinical information of limited diagnostic value. (Pircon et al., Amer. J. Obstet. Gynecol. 161:775, 1989) Copper et al. attempted to diagnose preterm labor using uterine activity (4 contractions/20 minutes or 8 contractions/60 minutes) coupled "with at least one of the following: ruptured membranes, cervical changes, cervical dilatation .gtoreq.2.0 cm, or cervical length .ltoreq.1.0 cm." Copper reported that this assessment was complicated by the fact that "contractions, regardless of the measure of frequency," normally increase during pregnancy.
The presence of advanced cervical dilatation (or effacement) is clinically important for determining risk of delivery (Morrison, Obstet. Gynecol. 76 (Suppl. 1) 55, 1990). Many clinical studies have demonstrated that cervical dilatation of greater than 3 cm is frequently associated with imminent delivery regardless of gestational age. Unfortunately, not all women with symptoms of threatened preterm delivery who ultimately deliver prematurely have advanced cervical dilatation when they present for emergency obstetrical care (Lockwood, N. Engl. J. Med. 325:669, 1991). Moreover, among the many clinical symptoms and signs associated with preterm labor or delivery, cervical dilatation is not necessarily the first clinical change noted. Typically, women with preterm labor who ultimately deliver prematurely seek obstetrical care for non-specific symptoms such as uterine activity, change in vaginal discharge, or abdominal discomfort which frequently precede cervical dilatation. Given the poor predictive power of these clinical signs and symptoms, "clinicians do not have a good discriminator of false versus true labor", resulting in as many as 50% of patients with "false" labor delivering early (Morrison et al., Amer. J. Obstet. Gynecol. 168:538, 1993).
In contrast, a more potent method of diagnosing patients at risk for preterm delivery is emerging. The presence of fetal fibronectin in cervical or vaginal secretions has been shown to be an accurate predictor for preterm delivery in women with symptoms suggestive of threatened preterm delivery (Lockwood et al., ibid.). A control group of women with uncomplicated pregnancies who delivered at term rarely had cervicovaginal concentrations of fetal fibronectin greater than 50 ng/ml at weeks 21-37 of gestation. In contrast, approximately 94% of women with preterm rupture of amniotic membranes had significantly elevated fetal fibronectin concentrations. But more importantly, about 50% of women with intact amniotic membranes and preterm uterine contractions had elevated concentrations of fetal fibronectin and more than 80% of these women delivered prematurely. Conversely, greater than 80% of women with intact membranes who did not have detectable cervicovaginal fetal fibronectin delivered at term. Thus, fetal fibronectin was demonstrated to be both a sensitive and specific predictor of preterm delivery.
Not surprisingly, the lack of available specific and sensitive indicators of preterm delivery risk among symptomatic women limits the ability of physicians to appropriately treat women judged to be at risk. In addition, there is considerable controversy in the obstetrical community regarding the therapeutic efficacy of available treatment regimens. Of course, assessment of any treatment regimen is complicated by the fact that perhaps as many as half of women diagnosed with preterm labor may not have the disease.
Effective and judicious treatment of preterm labor, especially in earlier gestation, is critical to the development of the fetus. As discussed above, births after 32-34 weeks of gestation are associated with lower rates of neonatal mortality and severe neonatal morbidity. Thus, prolongation of pregnancy and subsequent reduction of preterm delivery rates might be expected to lower neonatal morbidity and mortality. Unfortunately, in spite of the fact that obstetricians have identified more women as candidates for preterm labor treatment (known as tocolysis) over the last decade, the incidence of preterm delivery has actually increased over the same time span (Creasy, Amer. J. Obstet. Gynecol. 168:1223, 1993). The fact that the preterm delivery rate has not improved over the past decade is due not only to the inability of physicians to accurately identify patients truly in need of treatment but also to the failure of commonly available tocolytic drugs to impede the progress of labor.
Numerous controlled, clinical trials have been conducted to evaluate the clinical merits of various treatment regimens including bedrest, hydration, antibiotics, beta-adrenergic agonists, prostaglandin inhibitors, and calcium antagonists. The cumulative experience of these trials has clearly shown that common strategies for tocolytic intervention do not reproducibly prevent preterm delivery although they may be modestly effective for prolongation of pregnancy. Unfortunately, modest gains do not necessarily translate into improved neonatal outcome. As Creasy has noted, "numerous trials of prophylactic beta-adrenergic tocolytic usage with relatively low doses of medication have also not shown benefit in either singleton or multiple gestation".
The role of infection in preterm labor and use of antibiotics has been studied extensively, particularly in the context of premature rupture of the membranes (PROM). For example, a controlled clinical trial of antibiotic treatment with the broad spectrum erythromycin and ampicillin was associated with prolongation of gestation compared to the absence of antibiotics (McGregor and French, Obstet. Gynecol. Clin. North Amer. 19:327-38, 1992). In contrast, a controlled study of prophylactic erythromycin therapy showed no decrease in the incidence of maternal or neonatal infectious morbidity; however, in patients "destined to have chorioamnionitis and oligohydramnios", pregnancy was significantly prolonged (Mercer et al., Amer. J. Obstet. Gynecol. 166:794, 1992).
Only four trials evaluating the effect of antibiotics in treatment of women with preterm labor and intact membrances have been conducted. "Three of the four groups report an apparent prolongation of pregnancy with antibiotic therapy without impact on aggregate birth weight or perinatal mortality of the resultant infants" (Kirschbaum, Amer. J. Obstet. Gynecol. 168:1239, 1993). The results of these trials are difficult to interpret due to the use of different antibiotics, different clinical criteria for diagnosis of preterm labor and small numbers.
More promising strategies for reducing the incidence of preterm birth and lowering rates of neonatal morbidity and mortality may involve use of combination therapies, i.e., simultaneously using multiple, independent drugs. Kanayama (Nihon Sanka Fujinka Gakkai Zasshi. 44:110-15, 1992) reported a clinical study of women who showed signs of impending premature delivery. None of the patients had PROM, all were between the 24th and 35th weeks of pregnancy, and all had a "tocolysis index of 3-4", which was described as "imminent premature delivery of an intermediate degree." The tocolysis index is a relative index of delivery risk in which various risk factors for preterm delivery including status of amniotic membranes (rupture versus intact membranes), presence or absence of vaginal bleeding, estimation of cervical dilatation, and frequency of uterine contractions are semi-quantitatively assessed and scored, as indicated below.
______________________________________ Tocolysis Index 0 pts 1 pt 2 pts 3 pts ______________________________________ Cervical Dilation 0 cm 1 cm 2 cm 3 cm Vaginal Bleeding none -- spotting bleeding Ruptured Membranes intact -- -- rupture Uterine Activity none irreg. regular -- ______________________________________
The final tocolysis score represents the sum of each factor's "score" and hypothetically correlates to risk for preterm delivery as well as potential for successful tocolytic treatment. A tocolysis score of less than 3 indicates minimal risk for preterm delivery (and high probability of tocolytic success) while increasingly higher scores are associated with greater risk for preterm delivery (and lower probability of successful tocolytic intervention). While the tocolysis index is a modestly accurate method for assessing crude risk, it is neither reproducible between physicians (inter-observer error) nor a consistent predictor among individuals.
Kanayama and co-workers evaluated the effect of four therapeutic strategies on preterm delivery rate as well as cervical expression of granulocyte elastase, a putative mediator of the labor process. The four therapeutic regimens evaluated included ritodrine infusion only (Group A), daily urinastatin vaginal suppositories (Group B), combination of ritodrine infusion and vaginal urinastatin suppositories (Group C), and combination of ritodrine infusion, vaginal urinastatin suppositories, and systemic antibiotic therapy (Group D). When patients were treated with urinastatin (groups B, C and D), the elastase in vaginal secretions decreased. The time required for the number of uterine contractions (UC) to decrease to less than 1 per 30 minutes was about an hour for groups A, C and D; whereas this same UC decrease took an average of about 6 hours in group B (urinastatin alone). When UC had been depressed for 4 days, therapy was discontinued. Approximately 60% of the patients in group A experienced a recurrence; whereas, only 11-17% of the other groups experienced recurrent UC. In group A, 25% of women had premature deliveries, compared to no premature deliveries for groups B and D (9 and 8 patients, respectively) and only 1/14 in group C.
However, in the above studies, no subjects with PROM or with tocolytic scores over 4 were tested. The authors suggested that "in more advanced cases of imminent premature delivery, further studies will be needed, since it is believed that localized therapies alone are insufficient." Moreover, there was no difference between group C (ritodrine and urinastatin) and group D (ritodrine, urinastatin and antibiotic).
Fuzishiro et al. reported that a patient with history of habitual abortion was observed to have a protruding amniotic sac at 20 weeks of gestation. She was treated with vaginal antibiotics and urinastatin, tocolytics and bed rest. Her pregnancy was maintained up to 36 weeks. Japan. J. Obstet. Gynecol. Neonatal. Hematol. 2:107-10, 1992.
Urinastatin, whose use is described above, is purified from human urine. It has been reported to suppress IL-1.beta.-induced reduction of proteoglycan synthesis, superoxide generation, and inhibit a variety of serine proteases, such as trypsin, .alpha.-chymotrypsin, plasmin, leukocyte elastase and leukocyte cathepsin G.
Because urinastatin inhibits many chemical mediators in inflammation, urinastatin has been evaluated as an anti-inflammatory drug. Hence, urinastatin has been proposed for use in a variety of conditions, such as pancreatitis, septic shock, operative stress, arthritis, thrombosis and preterm delivery. It also has been proposed for use in disseminated intravascular coagulation. Inaba et al., Folia Pharmacol. Japon. 88: 239, 1986.
What is needed is an effective method to prolong pregnancy, prevent preterm delivery and reduce rates of neonatal morbidity and mortality in women with clinical signs of preterm labor.